Velocardiofacial syndrome (VCFS), caused by a microdeletion on chromosome 22q11.2 and affecting 1:4000 individuals, is associated with congenital anomalies, neurocognitive deficits, and, in up to 30% of adults with this syndrome, schizophrenia (SZ). We are only beginning to identify the factors that predict SZ n individuals with this genetic disorder. In this application, we are proposing to continue our longitudinal study of risk factors for psychosis in VCFS that we began in February of 2001. During the past 5 years, we have collected extensive neuroanatomic, cognitive, and psychiatric data at two time points on 83 youth with VCFS, 33 of their unaffected siblings and 38 community controls. These data have permitted us to begin to map the trajectory of cognitive, psychiatric and neuroanatomic development in children with VCFS, and to determine which of these factors predict poor psychiatric function at Time 2. However, the youth in our sample are just reaching the age at which they are most vulnerable to the onset of SZ. Accordingly, it is critical that we continue follow this cohort in order to identify the neuroanatomic and neuropsychological factors that are associated with, and may be predictive of, the onset of SZ. The goal of the proposed project is to extend our investigation of this large sample through a third phase of data collection, which will span the age range (15-21 years) during which youth with VCFS become vulnerable to the onset of SZ. We are proposing to apply advanced computational tools to analyze the cortical thickness and cortical morphology of the specific brain regions that we have found are altered in youth with VCFS and that may be associated with poor psychiatric function. We will then examine the effect of genotype, brain volumes, cortical surface morphology / thickness and neurocognitive function on psychiatric outcome. Our specific aims are: 1) to map the neuroanatomic, neurocognitive and psychiatric trajectory in youth with VCFS;to determine the extent to which the developmental trajectories of 2) specific brain volumes, cortical surface morphology and cortical thickness, 3) neuropsychological function, and 4) psychiatric disorders are associated with either premorbid or positive symptoms of SZ at Time 3;and 5) to determine whether allelic variation in the Val158Met COMT polymorphism predicts either premorbid or positive symptoms of SZ at Time 3. The high rate of SZ in VCFS constitutes a significant public health concern for both families and society. Identifying those factors that place youth with VCFS at the highest risk for SZ will impact positively on the early, preventative intervention and treatment of psychiatrically impaired children and youth with VCFS, thus reducing its toll on families and society.